bims-lypmec 2025-11-23 papers

bims-lypmec

Biomed News

on Lysosomal positioning and metabolism in cardiomyocytes

Issue of 2025–11–23
seven papers selected by
Satoru Kobayashi, New York Institute of Technology

Failure of lysosomal acidification and endomembrane network in neurodegeneration.
Non-canonical roles of lysosomes in neurons.
Deacetylation of HSC70 by SIRT2 promotes chaperone mediated autophagy.
Lysosomal acid lipase-1 functions in autophagy occurrence and lipid homeostasis dependent of heat shock protein 83 in insects.
Lysosome-Mediated Targeted Protein Degradation: Emerging Chimeric Platforms for Extracellular and Intracellular Therapeutics.
Membrane curvature: a key regulator of membrane protein structure and function.
Ferroptosis-related differentially expressed genes in patients with diabetes.

Exp Mol Med. 2025 Nov 18.

Failure of lysosomal acidification and endomembrane network in neurodegeneration.

Seo-Hyun Kim, Young-Sin Cho, Yong-Keun Jung.

Lysosomes have emerged as central hubs in the regulation of the endomembrane system, extending beyond degradation to coordinate organelle communication. Central to this regulatory role is vacuolar-type H+-ATPase (V-ATPase), a proton pump that acidifies the lysosomal lumen to enable hydrolase activity and support proteostasis. In addition to its lysosomal functions, V-ATPase influences the physiology of other organelles, including the endoplasmic reticulum (ER), Golgi apparatus and mitochondria, through both direct and indirect mechanisms involving acidification-dependent processes, such as protein folding, vesicular trafficking and stress responses. V-ATPase dysfunction compromises interorganelle communication through multiple mechanisms, including impaired calcium and lipid exchange at contact sites, disrupted organelle positioning and defective autophagic and stress signaling. In neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, V-ATPase impairment contributes to lysosomal storage pathology, ER stress, Golgi fragmentation and mitochondrial dysfunction. ER-endolysosome tethering proteins and mitochondria-lysosome contacts are particularly sensitive to pH and trafficking defects. These disruptions result in a cascade of organelle dysfunction and contribute to disease progression. Here, in this Review, we highlight how V-ATPase governs both local lysosomal function and broader organelle network integrity, positioning it as a critical regulator of endomembrane homeostasis and a potential therapeutic target in neurodegenerative conditions.

DOI: https://doi.org/10.1038/s12276-025-01579-x
Trends Neurosci. 2025 Nov 18. pii: S0166-2236(25)00222-X. [Epub ahead of print]

Non-canonical roles of lysosomes in neurons.

Jonathan I Spencer, Yulia Sudarikova, Michael J Devine.

  Neurons are highly polarised and compartmentalised cells with organelles that are specialised to support their spatial and functional demands. This includes lysosomes, which are single-membrane-bound organelles enveloping acidic contents enriched with hydrolytic enzymes. While classically thought to be localised at the soma where they degrade waste, lysosomes have a range of dynamic nondegradative functions throughout neurons. Here, we review lysosomal dynamics and non-canonical functions in neurons, including axonal mRNA transport, mammalian target of rapamycin (mTOR) and Ca2+ signalling, neuronal remodelling, and interorganellar contact sites. We synthesise work across a range of model systems and species, providing insights from neurological diseases, where previous lysosomal research has focussed on proteostatic failure. This perspective highlights the need to better define lysosomal heterogeneity, compartmentalisation and specialisation in neurons.

Keywords:  autophagy; neurodegeneration; neuronal plasticity; synapse; trafficking

DOI:  https://doi.org/10.1016/j.tins.2025.10.009
Autophagy Rep. 2025 ;4(1): 2580781

Deacetylation of HSC70 by SIRT2 promotes chaperone mediated autophagy.

Byunghyun Ahn, Wenzhe Chen, Wenbiao Shi, Ruben Shrestha, Fenghua Hu, Hening Lin.

  Chaperone-mediated autophagy (CMA) is a selective form of lysosomal protein degradation essential for cellular proteostasis. CMA is activated during cellular stress, such as starvation, and involves the chaperone protein HSC70 (HSPA8) recognizing substrates containing KFERQ-like motifs. However, the regulatory mechanisms governing CMA activation remain poorly understood. Here, we demonstrate that the NAD+ -dependent deacetylase SIRT2 promotes CMA activation by deacetylating HSC70 at lysine 557 (K557). Our findings reveal that SIRT2 activity is upregulated during starvation, enhancing its interaction with HSC70 and facilitating the deacetylation of K557. Deacetylation of HSC70 at K557 increases its binding affinity to CMA substrates, thereby promoting their lysosomal degradation. Mutation of K557 to a deacetylation-mimetic arginine (K557R) enhances CMA activity under both nutrient-rich and starvation conditions, while the acetylation-mimetic glutamine mutant (K557Q) impairs substrate binding and CMA activation. Furthermore, the inhibition or knockdown of SIRT2 reduces CMA activity, which is rescued by HSC70 K557R expression. These findings identify SIRT2-mediated deacetylation of HSC70 as a regulatory mechanism for CMA activation during nutrient deprivation and highlight the role of protein lysine acetylation in proteostasis. This study provides insights into the interplay between SIRT2, HSC70, and CMA, with potential implications for diseases linked to proteostasis dysregulation, including neurodegenerative disorders and cancer.

Keywords:  Chaperone-mediated autophagy; HSC70; KFERQ motif; SIRT2; amino acids starvation; deacetylation; heat shock chaperones; lysosomes; protein degradation; sirtuin

DOI:  https://doi.org/10.1080/27694127.2025.2580781
Insect Biochem Mol Biol. 2025 Nov 13. pii: S0965-1748(25)00191-2. [Epub ahead of print]186 104447

Lysosomal acid lipase-1 functions in autophagy occurrence and lipid homeostasis dependent of heat shock protein 83 in insects.

Peng Zeng, Xiaodong Li, Xuan Jin, Qien Zhong, Fareed Uddin Memon, Youliang Pan, Yang Xiao, Kang Li, Ling Tian.

  Lysosomal Acid Lipase (LAL) is the key enzyme responsible for hydrolyzing cholesteryl esters and triglycerides within lysosomes. Its dysfunction is linked to various metabolic disorders in humans. However, its biological functions display tissue-specific heterogeneity, and the roles of its homologs in invertebrates remain largely unexplored. Herein, we demonstrated the lysosomal localization of acid lipase-1 (BmAL1) in Bombyx mori through fluorescent protein observation and Co-immunoprecipitation with the lysosomal membrane glycoprotein BmLAMP1. BmAL1 overexpression promoted lysosomal acidification, enhanced autophagy, and reduced lipid droplet (LD) formation after oleic acid or palmitic acid treatment. Conversely, BmAL1 knockout or knockdown inhibited lysosomal acidification, autophagic flux, and lipid degradation. Subsequently, immunoprecipitation coupled with LC-MS analysis revealed that the BmAL1-interacting proteins were mainly associated with metabolic and human-disease pathways. Notably, functional disruption of BmAL1-interacting protein BmHSP83/BmHSP90 (heat shock protein) compromised BmAL1-mediated lysosomal acidification, autophagy induction, lipid metabolism, and the physical interaction between BmAL1 and BmLAMP1. These data fill a critical gaps in LAL research in invertebrates, and highlight potential targets for the utilization of beneficial insects and the development of pest control strategies.

Keywords:  Autophagy; BmAL1; BmHSP83; Lipid homeostasis; Lysosomal acidification

DOI:  https://doi.org/10.1016/j.ibmb.2025.104447
Drug Dev Res. 2025 Dec;86(8): e70197

Lysosome-Mediated Targeted Protein Degradation: Emerging Chimeric Platforms for Extracellular and Intracellular Therapeutics.

Shayan Asadi, Mina Taheri-Torbati, Prashant Kesharwani, Amirhossein Sahebkar.

  Targeted protein degradation (TPD) is an emerging drug discovery approach aimed at enabling the selective removal of disease-associated proteins. While proteolysis-targeting chimeras (PROTACs) have advanced intracellular degradation via the ubiquitin-proteasome system, their limitation to cytosolic proteins excludes ~40% of the human proteome that is extracellular or membrane-bound. Lysosome-targeting chimeras (LYTACs) address this gap by harnessing lysosomal trafficking receptors, thereby mediating the degradation of extracellular and membrane proteins. More recently, methylarginine-targeting chimeras (MrTACs) have extended lysosomal strategies to certain intracellular targets, bypassing proteasomal dependence. This review critically examines the mechanistic underpinnings, design strategies, and bioanalytical challenges associated with lysosome-mediated degradation platforms. Emphasis is placed on their therapeutic implications, analytical evaluation, and potential for expanding druggable targets. Together, these emerging lysosomal chimeras offer a paradigm shift in TPD, with far-reaching applications in precision medicine and chemical biology.

Keywords:  chimeric degraders; extracellular protein clearance; lysosome‐targeting chimeras (LYTACs); precision medicine; targeted protein degradation

DOI:  https://doi.org/10.1002/ddr.70197
Drug Discov Today. 2025 Nov 18. pii: S1359-6446(25)00263-6. [Epub ahead of print] 104550

Membrane curvature: a key regulator of membrane protein structure and function.

Pu Jiang, Cong Zhang, Cong Lin, Yibo Wang, Xiaohui Wang.

  Membrane curvature is a fundamental biophysical property that regulates the spatial organization, conformation and function of membrane-associated proteins, playing a crucial part in cellular signaling, material transport and membrane remodeling. Recent advances in imaging and computational technologies have deepened our understanding of the mechanisms driving membrane curvature and its influence on membrane protein function. In this review, we explore the key determinants of membrane curvature, its influence on the structure, function, localization, aggregation and dissociation of membrane proteins, and the experimental and computational strategies employed to investigate these interactions. Additionally, we discuss the therapeutic potential of targeting membrane curvature for disease treatment and outline current challenges and future research directions.

Keywords:  Membrane curvature; lipid–protein interaction; membrane dynamics; membrane proteins

DOI:  https://doi.org/10.1016/j.drudis.2025.104550
J Diabetes Metab Disord. 2025 Dec;24(2): 265

Ferroptosis-related differentially expressed genes in patients with diabetes.

Zhiyuan Li, Jianjun Yan, Ruiying Zhang, Yue Zheng, Bo Li.

   Background: Type 2 diabetes mellitus (DM) can lead to multiple organs damage, for instance, lower limbs, kidneys, nerves and heart. We aimed to investigate the differentially expressed genes (DEGs) that might be potential targets for DM patients, which may promote multiple organs damage.
Methods: GSE95849 and GSE25724 were downloaded and analyzed to obtain DEGs. A Venn diagram was used to obtain the overlapping ferroptosis-related DEGs using the Ferroptosis Database. Enrichment pathway analysis was performed and the hub genes were obtained. Pivotal miRNAs, transcription factors and drugs with the hub genes interactions were also predicted. Human blood samples were utilized to investigate the effects of the hub genes on DM progression.
Results: Utilizing the Limma package, 3796 up-regulated and 2475 down-regulated DEGs were obtained in GSE25724, while 5101 up-regulated and 842 down-regulated DEGs were obtained in GSE95849. Using Venn diagram, 28 ferroptosis-related DEGs were obtained. The list of ferroptosis-related DEGs was analyzed, which were involved in response to oxidative stress, cellular response to external stimulus, secondary lysosome, autophagosome, Prolactin signaling pathway, Ferroptosis, and IL-17 signaling pathway. In the protein-protein interaction network, the ferroptosis-related DEGs, including STAT3, SRC, MAPK3, CTBB, ELAVL1, PRKAA1, NFE2L2, PTGS2, MAPK1 and EIF2S1, were demonstrated the hub genes using MCC algorithm in CytoHubba plug-in. TFs interactions, miRNA interactions and drugs interactions with hub genes were explored, which demonstrated the drugs of the targets, for instance, PTGS2, RSG4, MAPK1, MAPK3 and PRKAA1.After validation of human blood samples, STAT3, CTBB, MAPK1 and EIF2S1 were validated to be highly expressed in diabetic patients compared to normal individuals.
Conclusions: The screened hub genes, STAT3, CTBB, MAPK1 and EIF2S1 were validated to be highly expressed in diabetic patients compared to normal individuals, which may be potential therapeutic targets to treat diabetes and improve patients' prognosis.
Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-025-01740-3.

Keywords:  Biomarkers; Diabetes mellitus; GSEA; Progression

DOI:  https://doi.org/10.1007/s40200-025-01740-3